The present invention relates to a controlled release formulation for the drug diltiazem or its pharmaceutically acceptable salts thereof and a method for manufacturing a controlled release dosage formulation containing diltiazem or a pharmaceutically acceptable salt thereof as the active ingredient.
Diltiazem hydrochloride, commonly referred to as diltiazem, is a benzothiazine derivative that blocks the influx of calcium ions in smooth and cardiac muscle and has few side effects. Diltiazem has been shown to be useful in alleviating symptoms of chronic heart disease, particularly angina pectoris, myocardial ischemia and hypertension. Diltiazem also has been shown to have activity against arrythmia and may be useful in treating congestive cardiac insufficiency, Raynaud""s syndrome and peripheral and cerebral circulatory insufficiency.
Diltiazem is sold commercially in extended release pharmaceutical dosage forms that attempt to maintain a therapeutic serum level of diltiazem and minimize the effects of missed doses of the drug caused by lack of patient compliance. One commercial form of extended release diltiazem is Cardizem CD(copyright). Cardizem CD(copyright) is described as a once-a-day extended release capsule containing diltiazem HCl and fumaric acid. In the prosecution history of U.S. Pat. No. 5,286,497, representations were made that the formulation disclosed in that patent is the formulation for Cardizem CD(copyright). The formulation for Cardizem CD(copyright) is identified in the prosecution history of U.S. Pat. No. 5,286,497 as having a xe2x80x9cstair step release profilexe2x80x9d that is created by a blend of two types of beads referred to as a rapid release bead and an extended release bead.
Another commercially available extended release form of diltiazem HCl is marketed under the trademark Dilacor XR(copyright). This formulation is described as a once-a-day capsule which contains multiple units of diltiazem HCl. The Dilacor XR(copyright) product is described in U.S. Pat. No. 4,839,177 which teaches that the tablets or multiple units which are placed in the capsule comprise a core of diltiazem HCl and a swellable polymer and a support platform applied to the tablet.
A third commercially available form of extended release diltiazem HCl is sold under the tradename Tiazac(trademark) or Viazem(trademark). U.S. Pat. No. 5,529,791 is listed with the United States Food and Drug Administration as relating to the Tiazac(trademark) product. U.S. Pat. No. 5,529,791 discloses an extended release form of diltiazem containing beads that comprise diltiazem HCl and a wetting agent. The beads are coated with a microporous membrane comprising a water soluble or water dispersible polymer and a water, acid and basic insoluble polymer.
Numerous other controlled release diltiazem formulations are in the prior art such as: U.S. Pat. No. 5,229,135 which discloses a once-a-day formulation containing a single pellet that is prepared with an active core coated with diltiazem and an inner and outer membrane surrounding the core; U.S. Pat. No. 4,960,596 which discloses a slow release preparation of diltiazem containing microgranules that comprise neutral excipients and diltiazem wherein the microgranules are coated with shellac and ethylcellulose; and Patent Cooperation Treaty Application No. WO 96/17598 which discloses a diltiazem formulation that is described as being suitable for once daily administration and contains three types of beads that release diltiazem at different time periods. Other diltiazem formulations are disclosed in U.S. Pat. Nos.: 4,721,619; 4,894,240; 5,002,776; 5,364,620; 4,891,230; 4,917,899; 5,288,505; 5,336,504; 5,470,584; 5,439,689; 5,376,384; 5,529,790; and 5,567,441.
It is an object of the present invention to provide a novel once-a-day diltiazem formulation that does not employ a mixture of the diltiazem and an organic acid or a wetting agent in the core.
It is also an object of the present invention to provide a novel process for manufacturing a once-a-day diltiazem formulation.
The foregoing objectives are meet by the present invention that is directed to a controlled release pharmaceutical dosage formulation comprising a plurality of active pellets coated with an extended release coating to form extended release pellets.
The active pellets comprises:
(i) 10-30% of a pharmaceutically acceptable inert seed;
(ii) 50-85% of diltiazem; and
(iii) 1-15% of a binder.
All the foregoing percentages are based upon the total weight of the active pellets.
The extended release coating comprises:
(i) 60-85% of a water insoluble water permeable polymer;
(ii) 0.5-5% of a water or acid soluble channeling agent;
(iii) 10-40% of a lubricant; and
(iv) optionally less than 1% of a surfactant.
All the foregoing percentages are based upon the total weight of the extended release coating.
The extended release coating can be applied to the active pellets by any means commonly used in the industry such as pan coating or air suspension techniques. It is preferred that the extended release coating be applied to the active pellets in a fluidized bed coater, preferably a Wurster type coater.
The controlled release pharmaceutical dosage formulation of the present invention can be administered to a patient in a free dosage form such as mixing a predetermined amount of the extended release pellets into food for administration or in a unit dosage form such as a gelatin capsule or tablet that contains a plurality of the extended release pellets.
The dosage formulation of the present invention may contain a homogeneous population of extended release pellets wherein each pellet comprises approximately the same amount or thickness of extended release coating. The dosage form of the present invention may also contain a heterogeneous population of extended release pellets wherein the population comprises a blend or mixture of pellets with different amounts or thicknesses of extended release coating.
A heterogeneous population of extended release pellets of the present invention can be obtained in a single batch intermittent coating process and thereby eliminate the need for several separate coating batches and a separate and distinct blending step. The unique process comprises adding a first allotment of active pellets to a coating equipment; coating the first allotment of active pellets with a first amount of extended release coating; adding a second allotment of active pellets to the coating equipment after the coating of the first allotment of active pellets with the first amount of extended release coating and coating the first and second allotment of active pellets with a second amount of extended release coating. Additional allotments, i.e. a third allotment or a fourth allotment, of active pellets may also be added to the coating equipment at subsequent time periods during the coating process and coating all the allotments of active pellets with additional amounts of extended release coating. Once the coating process is completed a heterogeneous population of pellets is obtained wherein the first allotment of active pellets has the greatest amount of or thickest extended release coating, the second allotment of active pellets are coated with less extended release coating than the first allotment, and the third allotment of active pellets, if employed, are coated with less extended release coating than the first and second allotments of active pellets.
The heterogeneous population of pellets prepared in accordance with the single batch intermittent process of the present invention has the advantage of eliminating the blending or mixing steps required to produce the bead blends of the prior art such as the Cardizem CD(copyright) product. The heterogeneous population also has the advantage of producing a population of pellets that provides a constant therapeutic amount of the diltiazem over a twenty-four hour period because each allotment of pellets will release the diltiazem at a different time period.